Objectives: Integrin αvβ6 is an epithelial-specific receptor that binds and activates latent transforming growth factor-β1 (TGF-β1). TGF-β1 has been implicated as an endogenous inducer of hair follicle regression during hair cycling. We found that β6 integrin knock-out (β6-/-) mice exhibited an accelerated wound repair and increased number of proliferating hair follicle keratinocytes compared to wild-type (WT) controls in a compromised wound healing model. This was associated with a reduced level of TGF-β1 activation. Therefore, we hypothesized that αvβ6 integrin-mediated TGF-β1 signaling regulates hair regeneration and the hair follicle involution process.
Methods: A standardized mouse model of depilation-induced hair cycling was established to trigger hair regeneration in WT and β6-/- mice. The expression and distribution of αvβ6 integrin were studied in regenerating hair follicles. The hair cycle stages were assessed at different time points. Catagen development was compared in the WT and β6-/- follicles. Keratinocyte proliferation, TGF-β1 expression, distribution and activation were assessed respectively.
Results: Integrin αvβ6 was strongly upregulated during hair regeneration in WT follicles and its expression was hair cycle stage dependent. β6-/- mice presented an accelerated hair regeneration compared to WT controls. Immunohistochemistry for the proliferating cell marker Ki67 indicated that β6-/- follicles contained significantly higher numbers of proliferating keratinocytes than WT follicles at an identical cycle stage. In addition, deletion of αvβ6 integrin retarded hair follicle regression. β6-/- follicles displayed significantly reduced levels of TGF-β1 expression and Smad2 phosphorylation during early anagen and the onset of catagen development compared to WT controls.
Conclusions: Loss of integrin αvβ6 causes enhanced keratinocyte proliferation and retarded hair follicle regression in vivo, which is associated with reduced TGF-β1 expression and activation in β6-/- follicles. This study suggests that suppressing αvβ6 integrin expression levels may have a clinical application in the treatment of human hair growth disorders.